Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content.
Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content.
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DOI：
10.1371/journal.pbio.2002907
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发表时间：
2018-04
期刊：
影响因子：
9.8
通讯作者：
Giacomini KM
中科院分区：
文献类型：
--
作者：
Liang X;Yee SW;Chien HC;Chen EC;Luo Q;Zou L;Piao M;Mifune A;Chen L;Calvert ME;King S;Norheim F;Abad J;Krauss RM;Giacomini KM
一系列代谢紊乱，包括肥胖、血脂失调和血糖水平升高，都与心血管疾病和糖尿病有关。最近发表的全基因组关联研究（GWAS）的数据分析表明，有机阳离子转运蛋白OCT1 （SLC22A1）的功能降低多态性与总胆固醇、低密度脂蛋白（LDL）胆固醇和甘油三酯（TG）水平升高以及2型糖尿病风险增加显著相关，但OCT1与这些代谢性状之间的联系机制仍然令人困惑。本研究表明，OCT1被广泛认为是一种药物转运体，在调节肝脏糖脂代谢中发挥关键作用，可能是通过介导硫胺素（维生素B1）的摄取及其在肝脏中的水平。小鼠中Oct1的缺失导致硫胺素依赖酶的活性降低，包括丙酮酸脱氢酶（PDH），这破坏了肝脏葡萄糖-脂肪酸循环，将能量生产来源从葡萄糖转移到脂肪酸，导致葡萄糖利用减少，糖异生增加，脂质代谢改变。反过来，这些影响导致全身肥胖和全身葡萄糖和脂质水平的增加。重要的是，野生型小鼠在硫胺素缺乏饮食（TDs）中表现出与Oct1缺乏小鼠表型相同的葡萄糖代谢受损。总之，我们的研究揭示了肝硫胺素缺乏症通过OCT1缺乏症在促进代谢不灵活性方面的关键作用，从而导致心脏代谢疾病的发病机制。肝脏是葡萄糖和脂质代谢的主要器官；肝脏能量代谢障碍常见于代谢性疾病。传统上，过量的宏量营养素（脂肪和葡萄糖）与代谢紊乱的发展有关。我们的研究提供了微量营养素维生素B1（硫胺素）失衡的证据，可以作为脂质和葡萄糖紊乱的病因，并涉及有机阳离子转运体OCT1在这些紊乱中。OCT1是肝脏中硫胺素水平的关键决定因素。在人类中，OCT1的功能减少多态性与高LDL胆固醇水平显著相关。使用Oct1基因敲除小鼠，我们发现肝脏中Oct1介导的硫胺素摄取减少导致硫胺素活性代谢物tpp水平降低，并降低关键的tpp依赖酶的活性。因此，从葡萄糖到脂肪酸氧化的转变发生，导致关键代谢中间体的失衡，代谢通量途径的改变和各种代谢调节机制的破坏。对Oct1基因敲除小鼠的广泛表征为各种代谢特征的分子机制提供了证据，并表明微量营养素失衡在心脏代谢疾病中的重要作用。
A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose–fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease. The liver is the major organ for glucose and lipid metabolism; impairment in liver energy metabolism is often found in metabolic disorders. Traditionally, excesses in macronutrients (fat and glucose) are linked to the development of metabolic disorders. Our study provides evidence that imbalances in a micronutrient, vitamin B1 (thiamine), can serve as an etiological cause of lipid and glucose disorders and implicates the organic cation transporter, OCT1, in these disorders. OCT1 is a key determinant of thiamine levels in the liver. In humans, reduced-function polymorphisms of OCT1 significantly associate with high LDL cholesterol levels. Using Oct1 knockout mice, we show that reduced OCT1-mediated thiamine uptake in the liver leads to reduced levels of TPP—the active metabolite of thiamine—and decreased activity of key TPP-dependent enzymes. As a result, a shift from glucose to fatty acid oxidation occurs, leading to imbalances in key metabolic intermediates, alterations in metabolic flux pathways, and disruptions of various metabolic regulatory mechanisms. The extensive characterization of Oct1 knockout mice provides evidence for the molecular mechanisms responsible for various metabolic traits and indicates an important role for imbalances in micronutrients in cardiometabolic disorders.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
7.7
作者：
Butler AA;Kozak LP
通讯作者：
Kozak LP
影响因子：
2.1
作者：
Fukuda T;Chidambaran V;Mizuno T;Venkatasubramanian R;Ngamprasertwong P;Olbrecht V;Esslinger HR;Vinks AA;Sadhasivam S
通讯作者：
Sadhasivam S
影响因子：
7.7
作者：
Holness, MJ;Kraus, A;Sugden, MC
通讯作者：
Sugden, MC
影响因子：
2.9
作者：
Hennig, J;Kern, G;Hübner, G
通讯作者：
Hübner, G